There is mounting evidence that some individuals are protected against HIV-1 infection. In a sex worker cohort from Nairobi, Kenya a subgroup of women show epidemiologic evidence for resistance to HIV-1 infection. In this cohort HIV-1 resistance correlates with T helper cell recognition of HIV-1 antigens, CTL to HIV-1, neutralizing HIV-1 specific mucosal IgA and HLA alleles, suggesting that resistance may be mediated by immune mechanisms. The potential role of the mucosal immune response to HIV-1 in protection against infection has been poorly studied. In this project, studies of mucosal immune mechanisms potentially mediating HIV-1 resistance will be expanded. There are two broad specific aims of these studies. The first is to understand what HIV-1 specific mucosal immune mechanisms occur in HIV-1 resistant women and the second is to understand why these responses develop. To examine what specific mucosal immune mechanisms occur in HIV-1 resistant women, the frequency and epitope specificity of HIV-1 specific IgA and HIV-1 specific CTL in the genital tract of resistant women will be determined. Studies will also address how HIV-1 specific responses in the genital tract change over time and with concomitant infections and with hormonal contraception in HIV-1 uninfected and resistant sex workers. To understand why mucosal immune responses develop in HIV-1 resistant women, studies to characterize the T helper cell response to HIV-1 in the genital tract will be carried out. The project will also examine immunogenetic influences on the development of mucosal immune responses by correlating immune effector responses to genetic factors linked to HIV-1 resistance. Finally HIV-1 specific antibody and CTL, T helper cell, dendritic cell response and immunoregulatory factors in the genital tract will be correlated with protection against HIV-1 infection and epidemiologic, reproductive and behavioral variables.